CAPITULO IV BENEFICIARIOS DEL EXTERIOR
SUJETOS, HECHO GENERADOR, FUENTE Y EXENCIONES
Predominantly Hyperfractionation: Phase I and II Studies
• In head and neck studies, 2 daily fractions of 1.1 to 1.2 Gy were used, with
interfraction intervals of 3 to 8 hours. Increased mucosal reactions were associated with improved tumor control; there was an increased risk of late complications with total doses over 76.8 Gy (17,21).
• In four brainstem glioma studies (2 daily fractions of 1.00 to 1.26 Gy, minimum 4-hour
interfraction interval), there was no increase in brainstem necrosis; median survival time improved in one study (14).
• In the RTOG 83-11 lung cancer study (2 daily fractions of 1.2 Gy, minimum 4-hour
interfraction interval, total doses of 60.0 to 79.2 Gy), no dose response for survival was noted; best survival (29% at 2 years) was with a total dose of 69.6 Gy in a subset of patients with favorable presentation. There was a trend toward an increased incidence of severe complications at the highest dose level (8).
• An RTOG bladder dose-escalation protocol (2 daily fractions of 1.2 Gy, minimum 4-
hour interfraction interval, total dose of 60.0 to 69.6 Gy) reported a 10% 2-year actuarial incidence of grade 3 and 4 late complications, suggesting that tolerance of pelvic organs may be significantly increased through hyperfractionation (3).
Predominantly Hyperfractionation: Phase III Studies
• Four prospective randomized phase III clinical trials were performed (three in head
and neck and one in urinary bladder) (3).
• In a study of T2-3N0-1 tumors of the oropharynx comparing 2 fractions of 1.15 Gy, 6-
to 8-hour interfraction interval, total dose of 80.5 Gy in 7 weeks versus 1 daily fraction of 2 Gy, total dose of 70 Gy in 7 weeks, with hyperfractionation, there was an
improved overall 5-year locoregional control rate (59%) (p = .02) (improvement in T3 but not in T2 primary tumors), improved overall survival (p = .08), and more severe mucosal reactions; late treatment-related morbidity was the same (12).
Type A: Continuous Short Intensive Courses
• In Burkitt's lymphoma, with 3 daily fractions of 1.00 to 1.25 Gy, there were greatly improved response rates compared with 1 daily fraction to similar total doses (16).
• With continuous hyperfractionated accelerated radiation therapy (CHART) for head
and neck cancer, primarily stage III or IV cancers of oral cavity, oropharynx, hypopharynx, and larynx, a short, intensive irradiation schedule was used (3 daily fractions of 1.5 Gy, 6-hour intervals, for 12 consecutive days, total dose of 54 Gy) (9). Three-year local tumor control was 49% compared to 36% in matched historic controls. Healing of acute reactions was delayed beyond 6 months in approximately 20%; late effects were no worse or were less severe than with conventional
fractionation, except for radiation myelitis (four patients with spinal cord doses of 45 to 48 Gy).
• In a phase III trial of CHART (66 Gy in 33 fractions in 6.5 weeks) versus conventional
fractionation in 918 patients with head and neck cancer, including all sites and stages except T1N0, there was no significant difference in tumor control or survival, although there was a trend for CHART to be more effective in achieving control of higher-stage
tumors (10). Acute mucosal reactions were more severe with CHART, although there
was no difference in late reactions; myelopathy did not occur when spinal cord dose was limited to 40 Gy.
• In a phase III postoperative accelerated fractionation study, patients with stage T3-
4N0-2 carcinomas of various head and neck sites were randomized, after surgical resection, to receive either 50 Gy in 25 fractions in 5 weeks, or 42 Gy in 30 fractions, 3 times a day with 4-hour intervals, in 11 days (4). Accelerated hyperfractionation was associated with higher actuarial disease-free survival and a lower late complication rate at 3 years in 56 patients and with higher survival in patients with fast-proliferating tumors (thymidine labeling index greater than10.4% or Tpot less than 4.5 days). The
overall late complication rate was very high (approximately 75%).
• A study of 103 patients with inoperable breast cancer treated with a short, intensive
course showed 34.6% tumor control at 5 years; significant late effects occurred when
total doses exceeded 45 Gy (18). In 42 patients with inflammatory breast cancer who
were treated with accelerated fractionation (51 to 54 Gy in 4 weeks, plus a boost), the locoregional control rate significantly improved over historic controls treated with protracted Baclesse technique (5).
• Two studies of non–small cell lung cancer treated with accelerated fractionation (66
Gy in 1.8 to 2.0 Gy fractions in 4 weeks [20] or the CHART regimen described earlier
[10]) reported encouraging tumor responses, but esophagitis was severe.
• In a randomized, phase III trial of non–small cell lung cancer patients with disease
apparently confined to chest, CHART was compared with conventional fractionation (60 Gy in 30 fractions in 6 weeks); there was a significant survival advantage with
CHART (30% 2-year rate versus 20% with conventional treatment) (3). Intrathoracic
tumor control was not significantly different. The incidence of severe dysphagia was 49% with CHART and 19% with conventional therapy.
Type C: Concomitant Boost
• In 79 patients with moderately advanced oropharyngeal primary lesions, overall 2-
year locoregional tumor control was 68%, with best results obtained when boost was given during the last 2.0 to 2.5 weeks of basic treatment course (2-year locoregional control of 78%). There was an increase in severe acute reactions but no increase in late treatment complications (2). In an update in 127 patients treated with
concomitant boost, delivered during the latter part of basic treatment, 4-year locoregional tumor control was 72%, increasing to 81% with surgical salvage (1).
• In a nonrandomized study of 100 patients, 50 received accelerated fractionation (total
(total dose of 70.6 Gy in 52 to 54 days); concomitant boost was given during the first and middle thirds of the basic treatment course. Significantly higher 3-year
locoregional control (62% versus 33%) and disease-specific survival (66% versus 38%) occurred with concomitant boost; there was increased acute toxicity in the accelerated fractionation group (13).
Quasi–Accelerated Fractionation
• In a prospective randomized trial of head and neck cancer, 1.6 Gy 3 times daily in
split course to 67.2 to 72.0 Gy in 6 to 7 weeks was compared with standard
fractionation; locoregional control and 3-year survival were identical in both arms. The increased incidence of late effects with the quasi-acceleration may be attributed to the 3-hour minimum interfraction interval (10).
• Prostate cancer patients treated with 3 daily fractions of 2 Gy (4-hour interfraction interval, total dose of 60 Gy in 6 weeks, with 1 or 2 treatment interruptions) had a high incidence of severe late complications (19).
Other Randomized Trials
• Although altered fractionation regimens have been the focus of intense study to
improve local-regional tumor control for radiation therapy of head and neck cancers, the results of a recently reported RTOG study were below expectations (11). In RTOG 9003, 1,073 patients with locally advanced head and neck cancer were randomly assigned to four different fractionation schemes: standard fractionation (70 Gy, 35 fractions, 7 weeks); hyperfractionation (81.6 Gy, 1.2 Gy per fraction, twice daily for 7 weeks); accelerated fractionation with split course (to 67.2 Gy, 1.6 Gy per fraction, twice daily for 6 weeks including a 2-week rest after 38.4 Gy); and
accelerated fractionation with concomitant boost (72 Gy, 1.8 Gy daily fraction and 1.5 Gy boost as a second daily treatment for the last 12 treatments over 6 weeks). Approximately 60% of patients analyzed had cancer in the oropharynx. With a median follow-up of 23 months, the results indicated a small but significantly better local-regional control in patients treated with hyperfractionation (54.4%) and accelerated fractionation with concomitant boost (54.5%) than those treated with standard fractionation (46%).
• In patients with locally advanced head and neck cancer, a combination of
hyperfractionated irradiation (75 Gy, 1.25 Gy twice a day) and cisplatin/5-fluorouracil chemotherapy (cisplatin 12 mg per m2 daily and fluorouracil 600 mg per m2 per day during weeks 1 and 6 of irradiation) was more efficacious than hyperfractionated irradiation alone (6). The relapse-free survival rate was higher in the combined- treatment group (61% versus 41%, p = .08). The rate of locoregional control of disease at 3 years was 70% in the combined-treatment group and 44% in the hyperfractionation group (p = .01).
Conclusions
• In some trials for head and neck cancer, altered fractionated schedules have proven
to be more efficacious than standard irradiation.
• In other tumors, altered fractionation schedules should be investigated in additional
clinical trials.
References
1. Ang KK, Peters LJ. Concomitant boost radiotherapy in the treatment of head and neck
2. Ang KK, Peters LJ, Weber RS, et al. Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys
1990;19:1339–1345.
3. Ang KK, Thames HD, Peters LJ. Altered fractionation schedules. In: Perez CA, Brady LW, eds. Principles and practice of radiation oncology, 3rd ed. Philadelphia: Lippincott–Raven,
1998:119–142.
4. Awwad HK, Khafaagy Y, Barsoum M. Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: influence of tumour
proliferation. Radiother Oncol 1992;25:261–266.
5. Barker JL, Montague ED, Peters LJ. Clinical experience with irradiation of inflammatory carcinoma of the breast with and without elective chemotherapy. Cancer 1980;45:625–
629.
6. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med
1998;338:1798–1804.
7. Budhina M, Skrk J, Smid L, et al. Tumor cell repopulation in the rest interval of split-course
radiation treatment. Strahlenther Onkol 1980;156:402–408.
8. Cox JD, Azarnia N, Byhardt RW. A randomized phase I/II trial of hyperfractionated therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non–small cell carcinoma: report of Radiation Therapy Oncology Group 83-11. J Clin Oncol 1990;8:1543–
1555.
9. Dische S, Saunders MI. The CHART regimen and morbidity. Acta Oncol 1999;38:147–
152.
10. Dische S, Saunders MI, Barrett A, et al. A randomized multicenter trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997;44:123–
136.
11. Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first
report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7–16.
12. Horiot JC, LeFur RN, Schraub S, et al. Status of the experience of the EORTC Cooperative Group of Radiotherapy with hyperfractionated and accelerated radiotherapy
regimes. Semin Radiat Oncol 1992;2:34–37.
13. Johnson C, Schmidt-Ullrich R, Wazer D. Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and
neck. Cancer 1992;69:2749–2754.
14. Linstadt DE, Edwards MSB, Prados M, et al. Hyperfractionated irradiation for adults with
brainstem gliomas. Int J Radiat Oncol Biol Phys 1991;20:757–760.
15. Million RR, Zimmerman RC. Evaluation of University of Florida split-course technique for
16. Norin T, Onyango J. Radiotherapy in Burkitt's lymphoma conventional or
superfractionated regime: early results. Int J Radiat Oncol Biol Phys 1977;2:399–406.
17. Parsons JT, Mendenhall WM, Stringer SP, et al. Twice-a-day radiotherapy for squamous cell carcinoma of the head and neck: the University of Florida experience. Head Neck
1993;15:87–96.
18. Svoboda VH, Krawczyk J, Krawczyk A. Seventeen years experience with accelerated radiotherapy for carcinoma of the breast. Int J Radiat Oncol Biol Phys 1992;24:65–71.
19. Vanuystel L, Ang K, Vandenbussche L, et al. Radiotherapy in multiple fractions per day for prostatic carcinoma: late complications. Int J Radiat Oncol Biol Phys 1986;12:1589–1595.
20. Von Rottkay P. Remissions and acute toxicity during accelerated fractionated irradiation
of non–small cell bronchial carcinoma. Strahlenther Onkol 1986;162:300–307.
21. Wendt CD, Peters LJ, Ang KK, et al. Hyperfractionated radiotherapy in the treatment of squamous cell carcinomas of the supraglottic larynx. Int J Radiat Oncol Biol Phys
1989;17:1057–1062.
22. Withers HR, Taylor JMF, Maciejewski B. The hazard of accelerated tumor clonogen
9: Physics of Brachytherapy